Discovery of ecnoglutide - A novel, long-acting, cAMP-biased glucagon-like peptide-1 (GLP-1) analog.

OBJECTIVE: Glucagon-like peptide (GLP)-1 is an incretin hormone that acts after food intake to stimulate insulin production, enhance satiety, and promote weight loss. Here we describe the discovery and characterization of ecnoglutide (XW003), a novel GLP-1 analog. METHODS: We engineered a series of GLP-1 peptide analogs with an alanine to valine substitution (Ala8Val) and a γGlu-2xAEEA linked C18 diacid fatty acid at various positions. Ecnoglutide was selected and characterized in GLP-1 receptor signaling assays in vitro, as well as in db/db mice and a diet induced obese (DIO) rat model. A Phase 1, double-blind, randomized, placebo-controlled, single (SAD) and multiple ascending dose (MAD) study was conducted to evaluate the safety, tolerability, and pharmacokinetics of subcutaneous ecnoglutide injection in healthy participants. SAD doses ranged from 0.03 to 1.0 mg; MAD doses ranged from 0.2 to 0.6 mg once weekly for 6 weeks (ClinicalTrials.gov Identifier: NCT04389775). RESULTS: In vitro, ecnoglutide potently induced cAMP (EC50 = 0.018 nM) but not GLP-1 receptor internalization (EC50 > 10 µM), suggesting a desirable signaling bias. In rodent models, ecnoglutide significantly reduced blood glucose, promoted insulin induction, and led to more pronounced body weight reduction compared to semaglutide. In a Phase 1 trial, ecnoglutide was generally safe and well tolerated as a once-weekly injection for up to 6 weeks. Adverse events included decreased appetite, nausea, and headache. The half-life at steady state ranged from 124 to 138 h, supporting once-weekly dosing. CONCLUSIONS: Ecnoglutide showed a favorable potency, pharmacokinetic, and tolerability profile, as well as a simplified manufacturing process. These results support the continued development of ecnoglutide for the treatment of type 2 diabetes and obesity.

A manikin-based assessment of loose-fitting powered air-purifying respirator performance at variable flow rates and work rates.

Loose-fitting powered air-purifying respirators (PAPRs) are used in healthcare settings, although barriers to routine, everyday usage remain, including usability concerns and potential interference with work activities. Loose-fitting PAPRs are approved by the National Institute for Occupational Safety and Health (NIOSH) and must meet minimum performance requirements, including a minimum airflow requirement of 170 L/min. One course of action to address usability concerns is to allow for the use of PAPRs designed with reduced airflow rates. The primary objective of this study was to assess the effect of PAPR flow rate and user work rate on PAPR performance, using a manikin-based assessment method. PAPR performance was quantified using the "Manikin Fit Factor" (mFF), a ratio of the challenge aerosol concentration to the in-facepiece concentration. Flow rates from 50-215 L/min and low, moderate, and high work rates were tested. Two models of NIOSH Approved loose-fitting facepiece PAPRs were tested, both having an Occupational Safety and Health Administration Assigned Protection Factor (APF) or expected level of protection, of 25. A two-way analysis of variance with an effect size model was run for each PAPR model to analyze the effects of work rate and flow rate on PAPR performance. Flow rate and work rate were found to be significant variables impacting PAPR performance. At low and moderate work rates and flow rates below the NIOSH minimum of 170 L/min, mFF was greater than or equal to 250, which is 10 times the OSHA APF of 25 for loose-fitting facepiece PAPRs. At high work rates and flow rates below 170 L/min, mFF was not greater than or equal to 250. These results suggest that some loose-fitting facepiece PAPRs designed with a flow rate lower than the current NIOSH requirement of 170 L/min may provide respirator users with expected protection at low and moderate work rates. However, when used at high work rates, some loose-fitting facepiece PAPRs designed with lower flow rates may not provide the expected level of protection.

Patient-specific, echocardiography compatible flow loop model of aortic valve regurgitation in the setting of a mechanical assist device.

Background: Aortic regurgitation (AR) occurs commonly in patients with continuous-flow left ventricular assist devices (LVAD). No gold standard is available to assess AR severity in this setting. Aim of this study was to create a patient-specific model of AR-LVAD with tailored AR flow assessed by Doppler echocardiography. Methods: An echo-compatible flow loop incorporating a 3D printed left heart of a Heart Mate II (HMII) recipient with known significant AR was created. Forward flow and LVAD flow at different LVAD speed were directly measured and AR regurgitant volume (RegVol) obtained by subtraction. Doppler parameters of AR were simultaneously measured at each LVAD speed. Results: We reproduced hemodynamics in a LVAD recipient with AR. AR in the model replicated accurately the AR in the index patient by comparable Color Doppler assessment. Forward flow increased from 4.09 to 5.61 L/min with LVAD speed increasing from 8,800 to 11,000 RPM while RegVol increased by 0.5 L/min (2.01 to 2.5 L/min). Conclusions: Our circulatory flow loop was able to accurately replicate AR severity and flow hemodynamics in an LVAD recipient. This model can be reliably used to study echo parameters and aid clinical management of patients with LVAD.

Laboratory assessment of bacterial contamination of a sterile environment when using respirators not traditionally used in a sterile field environment.

OBJECTIVE: During infectious disease outbreaks or pandemics, an increased demand for surgical N95s that create shortages and necessitate the use of alternative National Institute for Occupational Safety and Health (NIOSH)-approved respirators that do not meet the Food and Drug Administration (FDA) additional requirements. The objective of this research was to quantify the level of bacterial contamination resulting from wearing NIOSH-approved respirators lacking the additional protections afforded by surgical N95s. METHODS: Participants performed simulated healthcare tasks while wearing 5 different respirators approved by the NIOSH. Sterile field contamination resulting from use of a surgical mask cleared by the FDA served as a baseline for comparison with the NIOSH-approved respirators. RESULTS: The bacterial contamination produced by participants wearing the N95 filtering facepiece respirators (FFRs) without an exhalation valve, the powered air-purifying respirators (PAPRs) with an assigned protection factor of 25 or 1,000 was not significantly different compared to the contamination resulting from wearing the surgical mask. The bacterial contamination resulting from wearing the N95 FFR with an exhalation valve and elastomeric half-mask respirator (EHMR) with an exhalation valve was found to be statistically significantly higher than the bacterial contamination resulting from wearing the surgical mask. CONCLUSIONS: Overall, NIOSH-approved respirators without exhalation valves maintain a sterile field as well as a surgical mask. These findings inform respiratory guidance on the selection of respirators where sterile fields are needed during shortages of surgical N95 FFRs.

Association of Beneficiary-Level Risk Factors and Hospital-Level Characteristics With Medicare Part B Drug Spending Differences Between 340B and Non-340B Hospitals.

Importance: Critics of the federal 340B Drug Pricing Program raised concerns that the program might provide financial incentives for participating hospitals to prescribe more and/or more expensive drugs because the revenue generated from Medicare reimbursement exceeds the purchase price by a substantial margin. Studies showing higher Medicare Part B drug spending at hospitals that are 340B hospitals, which can purchase outpatient drugs from manufacturers at discounted prices, compared with non-340B hospitals were used by the Centers for Medicare & Medicaid Services to justify their 340B payment policy that reduced Medicare payments for drugs in the 340B program in 2018 and thereafter. The Centers for Medicare & Medicaid Services attributed higher spending to the 340B benefit and believed that payment cuts would reduce the financial incentives associated with higher spending. However, the lack of sufficient risk adjustments is a significant concern of study validity. Objective: To examine whether per-beneficiary Medicare Part B drug spending is significantly different between 340B and non-340B hospitals while adequately controlling for patient-level and hospital-level risk factors. Design, Setting, and Participants: A cross-sectional study was conducted from October 1, 2020, to May 30, 2021, using 2017 administrative claims data from a random 5% sample of Medicare fee-for-service beneficiaries. Included beneficiaries had at least 1 separately payable non-pass-through drug claim in 2017, were fully enrolled in Part A and Part B through 2017, and did not die in 2017. Main Outcomes and Measures: The outcome was separately payable Part B drug spending. Results: The sample included 35 364 beneficiaries (21 825 women [61.7%]; 29 996 White patients [84.8%]; mean [SD] age, 70.6 [12.0] years) and 2446 hospitals. A total of 918 hospitals (37.5%) were in the 340B program and 938 hospitals (38.3%) were teaching hospitals. There was a higher percentage of teaching hospitals among 340B hospitals (517 of 918 [56.3%]) than non-340B hospitals (421 of 1528 [27.6%]), and beneficiaries who went to 340B hospitals were more likely to be non-White than those who went to non-340B hospitals (3360 of 19 139 [17.6%] vs 1583 of 13 710 [11.5%]). The Part B drug spending difference between 340B and non-340B hospitals was not statistically significant after controlling for beneficiary-level risk factors and hospital-level characteristics ($568; 95% CI, -$283 to $1419; P = .19). Conclusions and Relevance: The results show that the differences in patient population and hospital-level characteristics may explain drug spending differences between 340B and non-340B hospitals, which raises doubt about the financial incentive theory of the 340B program drug discount and the justification for the Centers for Medicare & Medicaid Services's 340B payment policy.

Modeling and Analyzing for Thermal Protection of Firefighters' Glove by Phase Change Material.

Firefighter injures caused by burns and thermal stress occupies around 5%-10% of the total injuries annually. Glove is the thinnest/weakest components among the firefighter turnout gear, which can put firefighters, are at risk of severe wrist and hand burns during fire calls. Burns can occur quickly and enhancing the thermal protective performance of firefighters' gloves will prevent these burns. One-dimensional (1D) heat transfer modeling and simulations were performed through the COMSOL Multiphysics software to investigate the improvement of thermal protective performance when integrating a Phase Change Material (PCM) layer into a conventional structural firefighting glove. Parametric studies were conducted to explore the effects of PCM thermal properties, layer thickness, and location in glove structure on hand protection. It was found that a PCM with a higher density, specific heat, and latent heat of fusion had a larger heat capacity and thermal inertia, resulting in better thermal protective performance. The optimum melting point of PCM was found to be in the range of 80°C-140°C. A PCM layer with a thickness of 0.5 mm-1.0 mm showed sufficient thermal protection. The location of the PCM layer should be close to the inner glove surface for high-heat situations. Overall, modeling suggests that the addition of a PCM layer could significantly enhance the thermal protective performance of firefighters' gloves, with results showing increased time (2-4 times as long) for skin to reach second-degree burn temperature when compared to the conventional glove without PCM.

Comparison of ISO work of breathing and NIOSH breathing resistance measurements for air-purifying respirators.

The National Institute for Occupational Safety and Health's methods and requirements for air-purifying respirator breathing resistance in 42 CFR Part 84 do not include work of breathing. The International Organization for Standardization Technical Committee 94, Subcommittee 15 utilized work of breathing to evaluate airflow resistance for all classes of respiratory protective devices as part of their development of performance standards regarding respiratory protective devices. The objectives of this study were: (1) to evaluate the relationship between the International Organization for Standardization's work of breathing measurements and the National Institute for Occupational Safety and Health's breathing resistance test results; (2) to provide scientific bases for standard development organizations to decide if work of breathing should be adopted; and (3) to establish regression equations for manufacturers and test laboratories to estimate work of breathing measurements using breathing resistance data. A total of 43 respirators were tested for work of breathing at minute ventilation rates of 10, 35, 65, 105, and 135 liters per minute. Breathing resistance obtained at a constant flow rate of 85 liters per minute per National Institute of Occupational Safety and Health protocol was correlated to each of the parameters (total work of breathing, inhalation, and exhalation) obtained from the work of breathing tests. The ratio of work of breathing exhalation to work of breathing inhalation for all air-purifying respirators is similar to the ratio of exhalation to inhalation resistance when tested individually. The ratios were about 0.8 for filtering facepiece respirators, 0.5 for half-masks, and 0.25 for full-facepiece respirators. The National Institute for Occupational Safety and Health's breathing resistance is close to work of breathing's minute ventilation of 35 liters per minute, which represents the common walking/working pace in most workplaces. The work of breathing and the National Institute of Occupational Safety and Health's breathing resistance were found to be strongly and positively correlated (r values of 0.7-0.9) at each work rate for inhalation and exhalation. In addition, linear and multiple regression models (R-squared values of 0.5-0.8) were also established to estimate work of breathing using breathing resistance. Work of breathing was correlated higher to breathing resistance for full-facepiece and half-mask elastomeric respirators than filtering facepiece respirators for inhalation. For exhalation, filtering facepiece respirators were correlated much better than full-facepiece and half-mask elastomeric respirators. Therefore, the National Institute for Occupational Safety and Health's breathing resistance may reasonably be used to predict work of breathing for air-purifying respirators. The results could also be used by manufacturers for product development and evaluation.

New technique to evaluate decontamination methods for filtering facepiece respirators.

BACKGROUND: A major concern among health care experts is a shortage of N95 filtering facepiece respirators (FFRs) during a pandemic. One option for mitigating an FFR shortage is to decontaminate and reuse the devices. The focus of this study was to develop a new evaluation technique based on 3 major decontamination requirements: (1) inactivating viruses, (2) not altering the respirator properties, and (3) not leaving any toxic byproduct on the FFR. METHODS: Hydrophilic and hydrophobic FFRs were contaminated with MS2 virus. In the solution-based deposition, the virus-containing liquid droplets were spiked directly onto FFRs, while in the vapor-based and aerosol-based depositions, the viral particles were loaded onto FFRs using a bio-aerosol testing system. Ultraviolet germicidal irradiation (UVGI) and moist heat (MH) decontamination methods were used for inactivation of viruses applied to FFRs. RESULTS: Both UVGI and MH methods inactivated viruses (>5-log reduction of MS2 virus; in 92% of both method experiments, the virus was reduced to levels below the detection limit), did not alter the respirator properties, and did not leave any toxic byproduct on the FFRs. CONCLUSIONS: Both UVGI and MH methods could be considered as promising decontamination candidates for inactivation of viruses for respirator reuse during shortages.

Speech intelligibility test methodology applied to powered air-purifying respirators used in healthcare.

Powered air-purifying respirators (PAPRs) are worn to protect workers from hazardous respiratory exposures in a wide range of workplaces, including healthcare. However, PAPRs may diminish the ability of wearers to correctly hear words spoken by others, potentially interfering with safe performance of healthcare duties. Accordingly, the impact of PAPRs during healthcare use on speech intelligibility (SI) and consequently on user safety, usability, and patient care is not well studied. The objectives of this study were to (1) determine a listener's ability to comprehend single-syllable words spoken by a PAPR wearer; (2) determine a PAPR wearer's ability to intelligibly hear and identify single-syllable words spoken by a PAPR wearer; (3) to assess the variability between speakers, listeners, and PAPR models; (4) to investigate the effects of PAPR design features on SI; and (5) inform a SI requirement for certifying future PAPRs for use in healthcare. This study utilized a Modified Rhyme Test to assess SI for PAPRs. The current National Institute for Occupational Safety and Health (NIOSH) methods for assessing SI are limited to the recently introduced PAPR100 respirator class and the class of respirators claiming chemical, biological, radiological, and nuclear (CBRN) protections. Four NIOSH-approved PAPRs were evaluated using four human subjects. Four experimental conditions were examined:(1) Speaker and Listener with no PAPR; (2) Speaker and Listener both wearing PAPRs; (3) Speaker with a PAPR, Listener without a PAPR; and (4) Speaker without a PAPR, Listener with a PAPR resulted in a total of 144 experiments. Statistical analysis showed that the SI performance ratings were not significantly different among the PAPR models, but experimental conditions had significant impact on SI. The pattern of SI across the conditions of the experiment also showed a significant difference depending on PAPR model. The SI performance rating for all PAPRs could meet the current NIOSH CBRN certification requirement for speech intelligibility.

Assessment of respirator fit capability test criteria for full-facepiece air-purifying respirators.

An ASTM International subcommittee on Respiratory Protection, F23.65 is currently developing a consensus standard for assessing respirator fit capability (RFC) criteria of half-facepiece air-purifying particulate respirators. The objective of this study was to evaluate if the test methods being developed for half-facepiece respirators can reasonably be applied to nonpowered full-facepiece-air-purifying respirators (FF-APR). Benchmark RFC test data were collected for three families of FF-APRs (a one-size-only family, a two-size family, and a three-size family). All respirators were equipped with P100 class particulate filters. Respirators were outfitted with a sampling probe to collect an in-mask particle concentration sample in the breathing zone of the wearer. Each of the six respirator facepieces was tested on the National Institute for Occupational Safety and Health 25-subject Bivariate Panel. The RFC test assessed face seal leakage using a PortaCount fit test. Subjects followed the corresponding Occupational Safety and Health Administration-accepted fit test protocol. Two donnings per subject/respirator model combination were performed. The panel passing rate (PPR) (number or percentage of subjects in the panel achieving acceptable fit on at least one of two donnings) was determined for each respirator family at specified fit factor passing levels of 500, 1,000, and 2,000. As a reasonable expectation based on a previous analysis of alpha and beta fit test errors for various panel sizes, the selected PPR benchmark for our study was >75%. At the fit factor passing level of 500 obtained on at least one of two donnings, the PPRs for three-, two-, and one-size families were 100, 79, and 88%, respectively. As the fit factor passing criterion increased from 500 to 1,000 or 2,000, PPRs followed a decreasing trend. Each of the three tested families of FF-APRs are capable of fitting ≥75% of the intended user population at the 500 fit factor passing level obtained on at least one of two donnings. The methods presented here can be used as a reference for standards development organizations considering developing RFC test requirements.

Numerical Simulations of Exhaled Particles from Wearers of Powered Air Purifying Respirators.

In surgical settings, infectious particulate wound contamination is a recognized cause of post-operative infections. Powered air purifying respirators (PAPRs) are worn by healthcare workers for personal protection against contaminated aerosols. Healthcare infection preventionists have expressed concern about the possibility that infectious particles expelled from PAPR exhalation channels could lead to healthcare-associated disease, especially in operative settings where sterile procedural technique is essential. This study used computational fluid dynamics (CFD) modeling to simulate and visualize the distribution of particles exhaled by PAPR wearers. Using CFD simulations, the PAPR inside to outside ratio of particle concentrations was estimated. Also, the effects of particle sizes, supplied-air flow rates, and breathing work rates on outward leakage were evaluated. This simulation study reconstructed a geometrical model of a static median headform wearing a loose-fitting PAPR by capturing a 3D image. We defined a mathematical model for the headform and PAPR system and ran simulations with four particle sizes, three breathing workloads and two supplied-air flow rates (a total 24 configurations; 4×3×2=24) applied on the digital model of the headform and PAPR system. This model accounts for exhaled particles, but not ambient particles. Computed distributions of particles inside and outside the PAPR are displayed. The outward concentration leakage was low at surgical setting, e.g., it was about 9% for a particle size of 0.1 and 1 µm at light breathing and a 205 L/min supplied-air flow rate. The supplied-air flow rates, particle sizes, and breathing workloads had effects on the outward concentration leakage, as the outward concentration leakage increased as particle size decreased, breathing workload increased, and the supplied-air flow rate decreased. The CFD simulations can help to optimize the supplied-air flow rates. When the loose-fitting PAPR is used, exhaled particles with small size (below 1µm), or heavy breathing workloads, may generate a great risk to the sterile field and should be avoided.

COMPUTATIONAL FLUID DYNAMICS SIMULATION OF FLOW OF EXHALED PARTICLES FROM POWERED-AIR PURIFYING RESPIRATORS.

In surgical settings, infectious particulate wound contamination is a recognized cause of post-operative infections. Powered air-purifying respirators (PAPRs) are widely used by healthcare workers personal protection against infectious aerosols. Healthcare infection preventionists have expressed concern about the possibility that infectious particles expelled from PAPR exhalation channels could lead to healthcare associated infections, especially in operative settings where sterile procedural technique is emphasized. This study used computational fluid dynamics (CFD) modeling to simulate and visualize the distribution of particles exhaled by the PAPR wearer. In CFD simulations, the outward release of the exhaled particles, i.e., ratio of exhaled particle concentration outside the PAPR to that of inside the PAPR, was determined. This study also evaluated the effect of particle sizes, supplied air flow rates, and breathing work rates on outward leakage. This simulation study for the headform and loose-fitting PAPR system included the following four main steps: (1) preprocessing (establishing a geometrical model of a headform wearing a loose-fitting PAPR by capturing a 3D image), (2) defining a mathematical model for the headform and PAPR system, and (3) running a total 24 simulations with four particle sizes, three breathing workloads and two supplied-air flow rates (4×3×2=24) applied on the digital model of the headform and PAPR system, and (4) post-processing the simulation results to visually display the distribution of exhaled particles inside the PAPR and determine the particle concentration of outside the PAPR compared with the concentration inside. We assume that there was no ambient particle, and only exhaled particles existed. The results showed that the ratio of the exhaled particle concentration outside to inside the PAPR were influenced by exhaled particle sizes, breathing workloads, and supplied-air flow rates. We found that outward concentration leakage from PAPR wearers was approximately 9% with a particle size of 0.1 and 1 µm at the light breathing and 205 L/min supplied-air flow rates, which is similar to the respiratory physiology of a health care worker in operative settings, The range of the ratio of exhaled particle concentration leaking outside the PAPR to the exhaled particle concentration inside the PAPR is from 7.6% to 49. We found that supplied air flow rates and work rates have significant impact on outward leakage, the outward concentration leakage increased as particle size decreased, breathing workload increased, and supplied-air flow rate decreased. The results of our simulation study should help provide a foundation for future clinical studies.

Validation of Computational Fluid Dynamics Models for Evaluating Loose-Fitting Powered Air-Purifying Respirators.

Loose-fitting powered air-purifying respirators (PAPRs) are used in healthcare settings to reduce exposure to high-risk respiratory pathogens. Innovative computational fluid dynamics (CFD) models were developed for evaluating loose-fitting PAPR performance. However, the computational results of the CFD models have not been validated using actual experimental data. Experimental testing to evaluate particle facepiece leakage was performed in a test laboratory using two models of loose-fitting PAPRs. Each model was mounted on a static (non-moving) advanced headform placed in a sodium chloride (NaCl) aerosol test chamber. The headform performed cyclic breathing via connection to a breathing machine. High-efficiency particulate air (HEPA)-filtered air was supplied directly to the PAPR facepiece using laboratory compressed supplied-air regulated with a mass-flow controller. One model was evaluated with six supplied-air flowrates from 50-215 L/min (Lpm) and the other model with six flowrates from 50-205 Lpm. Three different workrates (minute volumes) were evaluated: low (25 Lpm), moderate 46 (Lpm), and high 88 (Lpm). Manikin penetration factor (mPF) was calculated as the ratio of chamber particle concentration to the in-facepiece concentration. Overall, data analyses indicated that the mPF results from the simulations were well correlated with the experimental laboratory data for all data combined (r = 0.88). For data at the three different workrates (high, moderate, low) for both models combined, the r-values were 0.96, 0.97, and 0.77, respectively. The CFD models of the two PAPR models were validated and may be utilized for further research.

Complication Rates, Hospital Size, and Bias in the CMS Hospital-Acquired Condition Reduction Program.

In 2016, Medicare's Hospital-Acquired Condition Reduction Program (HAC-RP) will reduce hospital payments by $364 million. Although observers have questioned the validity of certain HAC-RP measures, less attention has been paid to the determination of low-performing hospitals (bottom quartile) and the assignment of penalties. This study investigated possible bias in the HAC-RP by simulating hospitals' likelihood of being in the worst-performing quartile for 8 patient safety measures, assuming identical expected complication rates across hospitals. Simulated likelihood of being a poor performer varied with hospital size. This relationship depended on the measure's complication rate. For 3 of 8 measures examined, the equal-quality simulation identified poor performers similarly to empirical data (c-statistic approximately 0.7 or higher) and explained most of the variation in empirical performance by size (Efron's R2 > 0.85). The Centers for Medicare & Medicaid Services could address potential bias in the HAC-RP by stratifying by hospital size or using a broader "all-harm" measure.

Work of Breathing for Respiratory Protective Devices: Method Implementation, Intra-, Inter-Laboratory Variability and Repeatability.

As part of development of performance standards, the International Organization for Standardization (ISO) technical committee, ISO/TC 94/SC 15 Respiratory protective devices (RPD), adopted work of breathing (WOB) to evaluate airflow resistance for all designs (classes) of respiratory protective devices. The interests of the National Institute for Occupational Safety and Health's (NIOSH) National Personal Protective Technology Laboratory (NPPTL) are to compare the proposed WOB method and results for current RPD with those for present resistance methods. The objectives here were to assemble a method to meet the ISO SC15 standards, validate operation and conformance, and assess repeatability of WOB measurements for RPD. WOB method implementation and use followed standards ISO 16900-5:2016 and ISO 16900-12:2016. Volume-averaged total work of breathing (WOBT/VT where VT is tidal volume) determined for standard orifices was analyzed for variation and bias. After fabrication and assembly, the method gave preliminary verification orifice results that met ISO requirements and were equivalent to those from other laboratories. Evaluation of additional results from RPD testing showed tidal volume and frequency determined compliance. Appropriate adjustments reduced average absolute bias to 1.7%. Average coefficient of variation for WOBT/VT was 2.3%. Over 97% of results obtained during significant use over time met specifications. WOBT/VT for as-received air-purifying and supplied-air RPD were repeatable (p<0.05). WOBT/VT for unsealed half mask air-purifying RPD was an average of 31% lower compared to sealed. When experimental parameters were appropriately adjusted, the ISO WOB method implemented by NIOSH NPPTL consistently provided ISO-compliant verification WOBT/VT. Results for appropriately sealed RPD were reproducible.

Brief communication: prenatal and early postnatal stress exposure influences long bone length in adult rat offspring.

Stress during the prenatal and early postnatal periods (perinatal stress, PS) is known to impact offspring cognitive, behavioral, and physical development, but effects on skeletal growth are not clear. Our objective was to analyze effects of variable, mild, daily PS exposure on adult offspring long bone length. Twelve pregnant rat dams were randomly assigned to receive variable stress from gestational days 14-21 (Prenatal group), postpartum days 2-9 (Postnatal), both periods (Pre-Post), or no stress (Control). Differences in adult offspring tibia and femur length were analyzed among treatment groups. Mean tibia length differed among groups for males (P = 0.016) and females (P = 0.009), and differences for femur length approached significance for males (P = 0.051). Long bone length was shorter among PS-exposed offspring, especially those exposed to postnatal stress (Postnatal and Pre-Post groups). Results persisted when controlling for nose-tail length. These differences might reflect early stunting that is maintained in adulthood, or delayed growth among PS-exposed offspring. This study suggests that PS results in shorter long bones in adulthood, independently of effects on overall body size. Stunting and growth retardation are major global health burdens. Our study adds to a growing body of evidence suggesting that PS is a risk factor for poor linear growth.

Advancing return on investment analysis for electronic health record investment. Impacts of payment mechanisms and public returns.

This paper reviews a sample of studies reporting evidence on the implementation of electronic health record systems and identifies connections between reported benefits and hospitals' internal returns as well as public returns to external stakeholders, such as patients, the government and insurers. The study indicates that payment mechanisms play an important role in whether and to what extent reported benefits can be translated into a healthcare provider's financial profits. Under fee-for-service, reported benefits, such as reducing duplicate tests or improving preventive practice, will have a negative effect on a provider's financial performance. However, providers can realize those benefits financially under capitation. EHRs can improve clinician's compliance with pay-for-performance guidelines and promote the collection and report of quality data. But P4P's financial impact on EHR adoption is not clear. The study also suggests that returns from adopting EHRs can flow from the internal improvements in a healthcare entity resulting in returns to external stakeholders.

The development of new isoxazolone based inhibitors of tumor necrosis factor-alpha (TNF-alpha) production.

4-Aryl-3-pyridyl and 4-aryl-3-pyrimidinyl based tumor necrosis factor-alpha (TNF-alpha) inhibitors, which contain a novel isoxazolone five-membered heterocyclic core are described. Many showed sub-micromolar activity against lipopolysaccharide-induced TNF-alpha production.

The development of new bicyclic pyrazole-based cytokine synthesis inhibitors.

4-Aryl-5-pyrimidyl-based cytokine synthesis inhibitors of TNF-alpha production, which contain a novel bicyclic pyrazole heterocyclic core, are described. Many of these inhibitors showed low nanomolar activity against LPS-induced TNF-alpha production in a THP-1 cell-based assay and against human p38 alpha MAP kinase in an isolated enzyme assay. The X-ray crystal structure of a bicyclic pyrazole inhibitor co-crystallized with mutated p38 (mp38) is presented.